Pharmacogenomic Profiling of DPYD and UGT1A1 Variants and Prediction of Chemotherapy Toxicity in Patients with Advanced Colorectal Cancer: A Review

Abstract

Fluoropyrimidines and irinotecan carry a narrow therapeutic margin, and a minority of patients are genetically unable to clear them. Both vulnerabilitiesare detectable by a pre-treatment blood test. The evidence for acting on the DPYD result is now strong enough that  the remaining questions are about the size of the dose reduction rather than whether to test. Objectives: To review the published evidence on DPYD and UGT1A1 genotyping before chemotherapy for advanced colorectal cancer: which variants matter, how much toxicity they confer, what genotype-guided dosing achieves, and where the current dose recommendations fall short. Material and Methods: Narrative review of prospective genotyping studies, pharmacogenetic cohorts, meta-analyses and consensus dosing guidance indexed in PubMed and the major oncology and pharmacology journals. Studies were eligible if they reported the association between a DPYD or UGT1A1 variant and chemotherapy toxicity, or the outcome of genotype-guided dosing, in a defined population. No new patient data were generated; every estimate quoted is one published by the original investigators. Results: Severe fluoropyrimidine toxicity occurs in up to 30 per cent of treated patients. In a prospective study applying genotype-guided dose reduction, the relative risk of severe toxicity in DPYD*2A carriers fell to 1.31 (95% CI 0.63-2.73) from 2.87 (2.14-3.86) in a historical full-dose cohort, and no severe toxicity occurred in c.1679T>G carriers against a historical risk of 4.30 (2.10-8.80). The reduction was not uniformly sufficient: a 50 per cent reduction lowered severe toxicity in c.1905+1G>A carriers from 73 to 18 per cent, while a 25 per cent reduction left residual rates of 39 per cent in c.1236G>A and 47 per cent in c.2846A>T carriers. For irinotecan, UGT1A1*28 homozygosity carried an odds ratio for neutropenia of 4.79 (3.28-7.01) against wild type, and febrile neutropenia occurred in 18.2 per cent of homozygotes against 1.5 per cent of wild-type patients. Conclusion: DPYD genotyping before fluoropyrimidine treatment is supported by prospective evidence and should be routine. The dose reductions currently recommended are adequate for the loss-of-function alleles and demonstrably insufficient for the two reduced-function alleles. UGT1A1 testing
has a weaker evidence base, with a clear toxicity association but limited prospective evidence that upfront dose reduction improves outcome. Abbreviations: DPD – Dihydropyrimidine Dehydrogenase, DPYD – Dihydropyrimidine Dehydrogenase Gene, UGT1A1 – UDP Glucuronosyltransferase 1A1, 5-FU – Fluorouracil, SN-38 – Active Metabolite of Irinotecan, CRC – Colorectal Cancer, RR – Relative Risk, OR – Odds Ratio, CTCAE – Common Terminology Criteria for Adverse Events, CPIC – Clinical Pharmacogenetics Implementation Consortium, DPWG – Dutch Pharmacogenetics Working Group, AUC – Area Under the Concentration Curve.